ABSTRACT. The goal of this application is to use a mouse model to elucidate the mechanisms by which estrogen action, by way of the estrogen receptor(ER)s, improves islet oxygenation, revascularization and functional mass during pancreatic islet transplantation (PIT). Improving PIT outcome in type 1 diabetes (T1D) is a major goal of the NIH. We must explore new, simple and safe therapeutic approaches to suppress islet apoptosis while promoting islet oxygenation and revascularization in the immediate post-transplant period. Our laboratory was the first to show that the female hormone 17?-estradiol (E2) protects islet ?-cells from apoptosis via estrogen receptors and in human islets. Our new preliminary data demonstrates that E2 enhances islet oxygenation, revascularization and functional mass during PIT. We need to identify the actual cellular targets and molecular pathways used by ERs to promote these actions. The specific aims of this application are to 1) Elucidate the role ERs activation in graft ?-cells to islet engraftment using mice with conditional null allele of ERs in these cells (?ERKO). We will explore a novel paradigm in which paradigm that ER? activation in graft ?-cells programs islet metabolism by way of AMP-activated protein kinase (AMPK) and away from hypoxia-inducible factor-1 (HIF1) to improve islet performance during hypoxia. 2) Define the contribution of ERs activation in recipient endothelial cells to islet engraftment using mice with conditional null allele of ERs in these cells (VENERKO). We will explore a novel concept in which ER? activation in recipient mouse endothelial cells promotes acute vasodilation and oxygenation via endothelial nitric oxide synthase (eNOS) and delayed revascularization by way of vascular endothelial growth factor-A (VEGF-A).